Study of IDO Inhibitor in Combination With Checkpoint Inhibitors for Adult Patients With Metastatic Melanoma

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To evaluate the preliminary efficacy of the established dose of indoximod in combination with immune checkpoint inhibition as measured by the best overall response rate (ORR) (complete response (CR) + partial response (PR))across both standard of care agents administered sequentially in patients with unresectable stage III or stage IV melanoma

Condition or disease

Intervention/treatment

Phase

Metastatic MelanomaStage III MelanomaStage IV Melanoma

Drug: IndoximodDrug: IpilimumabDrug: NivolumabDrug: Pembrolizumab

Phase 1Phase 2

Detailed Description:

The incidence of melanoma is increasing. Based upon data obtained between 2004 and 2006, the lifetime probability of developing melanoma in the United States is estimated to be 1 in 37 for men and 1 in 56 for women. In the United States, melanoma is the fifth leading cancer in men and the seventh in women. Locally confined, fully-resectable disease may be curable with current therapy; but Stage IV metastatic disease (or relapsed/recurrent disease) is highly refractory to therapy. Thus, experimental clinical trials provide an accepted treatment option for metastatic or relapsed/refractory melanoma.

The current study is designed as a prospective trial to evaluate the combination of indoximod and checkpoint inhibitors in adult patients with metastatic melanoma. Ipilimumab, pembrolizumab and nivolumab will be used at the recommended approved doses for this indication.

The current trial will be done in two phases: a Phase 1b dose escalation of indoximod in combination with ipilimumab, starting at half the recommended single-agent dose, to establish the recommended Phase 2 dose for the combination.

This will be followed by a three arm expansion study testing a fixed dose of indoximod (at the recommended Phase 2 dose) combined with standard-dose ipilimumab, pembrolizumab or nivolumab.

Treatment will be administered on an outpatient basis. No investigational or commercial cancer directed agents or therapies other than those described below may be administered.

Safety assessment will follow the guidelines provided in the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version.4.03.

Patients will be followed both clinically and radiographically starting 12 weeks after initiation of treatment then every 8 weeks for tumor evaluation. Post-treatment scans will be compared to the baseline scan and responses will be assessed based using mWHO and immune related response criteria (irRC) described by Wolchok et al. (Wolchok et al., 2009).

Ipilimumab administered intravenously at 3 mg/kg every three weeks for a total of four doses.

Indoximod and ipilimumab will be dosed concurrently. Indoximod will be dosed twice daily on all days of each 21 day cycles (segment 1). Ipilimumab will be dosed on the 1st day of each 21 day cycle for the first 4 cycles. Indoximod dosing will continue after all 4 doses of ipilimumab are administered (segment 2, 28-day cycles).

Patients will continue until they experience disease progression or limiting toxicity.

Drug: Indoximod

Initial dose of 600mg BID by mouth with escalation planned to 1200mg BID by mouth

Dose escalation:

If 0 of the 3 subjects forming the first cohort experience RLT, 1200mg BID cohort will be enrolled

If 1 of the 3 subjects in any cohort experiences a RLT, then enrollment into that cohort will increase to a total of 6 subjects

If > 1 of the 3-6 subjects experience a RLT, then the MTD has been exceeded and further enrollment into the cohort will cease

If >1 subject at 600mg BID experiences a RLT, the dose will be de-escalated to 400mg BID. If >1 subject at this level experiences a RLT, one additional de-escalation to 200mg BID is allowed

Dosing cycles are 21 days in length during the combination immunotherapy component (first 4 cycles) and 28 days during indoximod monotherapy. Patients will continue until they experience disease progression or limiting toxicity

Ipilimumab administered intravenously at 3 mg/kg every three weeks for a total of four doses.

Other Names:

YERVOY

MDX-010

MDX-101

Experimental: Indoximod + Pembrolizumab

Indoximod will be administered at 1200mg BID by mouth.

Pembrolizumab administered intravenously at 2 mg/kg every three weeks

Drug: Indoximod

Initial dose of 600mg BID by mouth with escalation planned to 1200mg BID by mouth

Dose escalation:

If 0 of the 3 subjects forming the first cohort experience RLT, 1200mg BID cohort will be enrolled

If 1 of the 3 subjects in any cohort experiences a RLT, then enrollment into that cohort will increase to a total of 6 subjects

If > 1 of the 3-6 subjects experience a RLT, then the MTD has been exceeded and further enrollment into the cohort will cease

If >1 subject at 600mg BID experiences a RLT, the dose will be de-escalated to 400mg BID. If >1 subject at this level experiences a RLT, one additional de-escalation to 200mg BID is allowed

Dosing cycles are 21 days in length during the combination immunotherapy component (first 4 cycles) and 28 days during indoximod monotherapy. Patients will continue until they experience disease progression or limiting toxicity

Initial dose of 600mg BID by mouth with escalation planned to 1200mg BID by mouth

Dose escalation:

If 0 of the 3 subjects forming the first cohort experience RLT, 1200mg BID cohort will be enrolled

If 1 of the 3 subjects in any cohort experiences a RLT, then enrollment into that cohort will increase to a total of 6 subjects

If > 1 of the 3-6 subjects experience a RLT, then the MTD has been exceeded and further enrollment into the cohort will cease

If >1 subject at 600mg BID experiences a RLT, the dose will be de-escalated to 400mg BID. If >1 subject at this level experiences a RLT, one additional de-escalation to 200mg BID is allowed

Dosing cycles are 21 days in length during the combination immunotherapy component (first 4 cycles) and 28 days during indoximod monotherapy. Patients will continue until they experience disease progression or limiting toxicity

Overall Incidence of Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 17 months ]

Phase 1 component:

Evaluate the safety (adverse events - type, incidence, severity, duration, causality and treatment intervention) of the combination of indoximod and ipilimumab when given concomitantly.

The safety and tolerability ipilimumab followed by Indoximod will be assessed by listing the overall incidence of AEs. The AEs will be summarized and classified by body system and by treatment group. The type, incidence, severity, and causality of each AE, the duration of the event, and any required treatment interventions will be tabulated. Physical examination results will be presented in the patient data listings. The DLT will be listed per dose level and treatment along with overall frequencies. The data from the expansion part (Phase II) will be used for this part of safety and tolerability assessment.

Phase 2 Dosing [ Time Frame: 22 months ]

Phase 1 component:

To determine the recommended Phase 2 dose of indoximod in combination with ipilimumab in patients with unresectable melanoma.

A minimum of nine patients will be treated depending on DLT. Each dose will be administered to a cohort of 3 patients. If 0 out of 3 or less than 2 out of 6 patients experienced a DLT at any given dose level, the dose escalation will proceed to the next dose level. The MTD is generally the largest dose level at which at most 1 out of 6 patients experiences a DLT. IF DLT is not reached at the highest dose level (1200mg twice daily), no further escalation will proceed and this dose level will be declared the recommended Phase II dose

Overall Response Rate [ Time Frame: 22 months ]

Phase 2 component:

To evaluate the preliminary efficacy of the established dose of indoximod in combination with immune checkpoint inhibition as measured by the best overall response rate in patients with unresectable Stage III or Stage IV melanoma.

Secondary Outcome Measures
:

Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 22 months ]

Adverse event profile of ipilimumab and indoximod in patients with unresectable stage III or Stage IV melanoma participating in phase II portion of the study will be listed, summarized classified by body system. The type, incidence, severity, and causality of each AE, the duration of the event, and any required treatment interventions will be tabulated. Physical examination results will be presented in the patient data listings. The data from the expansion part (Phase II) will be used for this part of safety and tolerability assessment

Overall Survival [ Time Frame: 24 months ]

b) To evaluate the overall survival (OS) of patients with unresectable stage III or Stage IV melanoma receiving ipilimumab and indoximod. OS, defined as the time between the first dose of study therapy and death (subjects who have not died will be censored at the most recent last-known-alive date), will also be analyzed. The OS rate along with its 95% confidence interval will be presented.

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Ages Eligible for Study:

18 Years and older (Adult, Senior)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Unresectable Stage III or Stage IV melanoma.

Patients must have measurable disease, defined as lesions that can be accurately measure in in 2 perpendicular diameters with at least one diameter > 20mm and the other >10mm on conventional CT or MRI or 10mm x 10 mm by spiral CT.

No systemic treatment in the previous 28 days.

Age ≥18 years. Because no dosing or adverse event data are currently available on the use of ipilimumab or indoximod in patients <18 years of age, children are excluded from this study.

ECOG performance status ≤2 (Karnofsky ≥60% )

Patient has adequate bone marrow and organ function as defined by the following laboratory values :

Patients with known brain metastases will only be eligible after their tumors have been treated with definitive resection and/or radiotherapy and they are neurologically stable for at least 1 month off steroids.

The effects of indoximod on the developing human fetus are unknown. For this reason and because indoximod may affect maternal immune tolerance of the fetus, sexually active women of child-bearing potential must agree to use two forms of contraception (hormonal and barrier method of birth control or abstinence) prior to study entry and for the duration of study participation. Use of contraception or abstinence should continue for a minimum of 1 month after completion of the study. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should discontinue the study drug and inform her treating physician immediately. A pregnancy test is required prior to study enrollment and monthly while on treatment with indoximod for all women of child-bearing potential. Also men should be discouraged from fathering children while on treatment.

Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

Patients who have had molecular targeted therapy (including vemurafenib) or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.

Patients who have had prior therapy with immune checkpoint inhibition or or indoximod are excluded from the trial. Pre-treatment with other immune modulators is allowed in the phase 1 component of the study only. For the Phase II component, patients are excluded if they have had prior therapy with or immune-stimulating agents including interleukin-2, interferons, CTLA-4 or PD1 antagonists, CD40 or CD137 agonist, or cancer therapeutic vaccines in any prior line for metastatic disease. Interferons used in the adjuvant setting are allowed (Phase 1 or 2 component).

Patients with known active, uncontrolled brain metastases should be excluded from this clinical trial.

History of allergic reactions attributed to compounds of similar chemical or biologic composition to ipilimumab or tryptophan containing substances. This would include L-tryptophan or 5-hydroxy-tryptophan supplements. Also patients with a history of known hypersensitivity reactions to mouse or humanized monoclonal antibodies are excluded.

Pregnant women are excluded from this study because indoximod is an immunoregulatory agent with the potential for abortifacient effects due to fetal rejection by the maternal immune system. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with indoximod, breastfeeding should be discontinued if the mother is treated with indoximod.

Known HIV-positive patients and those with other acquired/inherited immunodeficiencies are ineligible due the possibility of affecting the response to indoximod, and the higher risk of active opportunistic infections.

Any other cancer, unless the patient has been disease-free for ≥5 years (except treated and cured basal-cell or squamous-cell skin cancer, superficial bladder cancer, or treated carcinoma in situ of the cervix, breast, or bladder and treated localized prostate cancer with undetectable PSA for 2 years).

Patients with laboratory evidence of pancreatitis are excluded.

Patients with autoimmune disease (e.g., psoriasis, extensive atopic dermatitis, asthma, IBD, M.S., uveitis, vasculitis), chronic inflammatory condition, or any condition requiring concurrent use of any systemic immunosuppressants or steroids for any reason are excluded from the study. Patients with isolated vitiligo remain eligible. Any patient with an allo-transplant of any kind would be excluded as well, including xenograft heart valve. Mild, intermittent asthma requiring only occasional beta-agonist inhaler use or mild localized eczema will not be excluded.

Chronic use of immune-suppressive drugs (ie, systemic corticosteroids used in the management of cancer or non-cancer related illnesses, eg, COPD).